The present invention relates to novel fused tricyclic nitrogen containing herterocycles, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists. This invention also relates to novel intermediates used in the synthesis of such substance P receptor antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract such as ulcerstive colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache,"edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).
In the recent past, some attempts have been made to provide antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above.
Quinuclidine derivatives and related compounds that exhibit activity as substance P receptor antagonists we referred to in Published PCT International Patent Application No. PCT/US89/05338, filed Nov. 20, 1989, now Published PCT International Patent Application No. WO90/06729 (published May 31, 1990) and now also U.S. Pat. No. 5,162,339.
Piperidine derivatives and related heterocyclic nitrogen-containing compounds that are useful as substance P receptor antagonists are referred to in PCT International Patent Application No. PCT/US90/00116, filed Jan. 4, 1990, which is now Published POT International Patent Application No, W091/09844 (published Jul. 11, 1992).